Targeting the c-Kit Promoter G-quadruplexes with 6-Substituted Indenoisoquinolines

Area of Science:

• Medicinal Chemistry
• Molecular Biology
• Oncology

Background:

• G-quadruplex DNA structures are crucial in gene regulation and cancer.
• Targeting G-quadruplexes with small molecules is a promising therapeutic strategy.
• Developing novel G-quadruplex stabilizing ligands is an active area of research.

Purpose of the Study:

• To design, synthesize, and evaluate 6-substituted indenoisoquinolines as novel G-quadruplex stabilizing ligands.
• To assess the biophysical properties and G-quadruplex stabilization potential of these compounds.
• To investigate the preliminary biological activity of indenoisoquinolines in cancer cells.

Main Methods:

• Synthesis of 6-substituted indenoisoquinolines (1a-e) in two steps.
• Evaluation of G-quadruplex stabilization using fluorescence resonance energy transfer-melting analysis.
• Assessment of cell growth inhibition in GIST882 tumor cell line.
• Analysis of c-Kit transcription and KIT oncoprotein levels.

Main Results:

• Indenoisoquinolines were synthesized in excellent yields.
• Compounds demonstrated significant stabilization of various G-quadruplex DNA structures.
• Indenoisoquinolines potently inhibited cell growth in the GIST882 cell line.
• Inhibition of c-Kit transcription and KIT oncoprotein levels was observed.

Conclusions:

• 6-substituted indenoisoquinolines represent a new class of potent G-quadruplex stabilizing ligands.
• These compounds exhibit promising anti-cancer activity through G-quadruplex stabilization and c-Kit pathway inhibition.
• Indenoisoquinolines warrant further investigation as potential therapeutic agents for GIST and other cancers.